Hypercholesterolemia is known to be one of the prime risk factors for ischemic cardiovascular disease, such as arteriosclerosis. Bile acid sequestrants have been used to treat this condition; they seem to be moderately effective but they must be consumed in large quantities, i.e. several grams at a time, and they are not very palatable.
MEVACOR.RTM. (lovastatin), now commercially available, is one of a group of very active antihyperchlolesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG-CoA reductase. In addition to the natural fermentation products, mevastatin and lovastatin, there are a variety of semi-synthetic and totally synthetic analogs thereof.
The naturally occurring compounds and their semi-synthetic analogs have the following general structural formulae: ##STR2## wherein: R.sup.1 is hydrogen, C.sub.1-5 alkyl or C.sub.1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino, or acetylamino; and
R* is ##STR3## wherein Q is ##STR4## or R.sup.3 --CH; R.sup.3 is H or OH; M is ##STR5## R.sup.4 is hydrogen or hydroxy; X is CR.sup.5 R.sup.6, O, S, or NH; R.sup.5 and R.sup.6 are H, OH, or OR.sup.7 where R.sup.7 represents a phosphoryl or acyl moiety; PA0 R.sub.2 and R.sub.3 are each independently selected from the group consisting of: PA0 R.sub.6 is selected from PA0 provided that when R.sub.2 or R.sub.3 is OH or OR.sub.5, the other is H, alkyl or arylalkyl and provided that both R.sub.2 and R.sub.3 are not H; PA0 R.sub.4 is PA0 X and Y are independently selected from PA0 Z is selected from PA0 R.sub.1 is selected from: PA0 R.sub.2 and R.sub.3 are each independently selected from the group consisting of: PA0 R.sub.6 is selected from PA0 R.sub.4 is: PA0 X and Y are independently selected from: PA0 R.sub.1 is C.sub.1-10 alkyl; PA0 R.sub.4 is H, CH.sub.3, CH.sub.2 OH or OH. PA0 (a) OH PA0 (b) OR.sub.5, or PA0 (c) R.sub.6 ; PA0 R.sub.5 is ##STR23## C.sub.1-5 alkyl or phenylC.sub.1-3 alkyl; R.sub.7 and R.sub.8 are H, C.sub.1-3 alkyl, phenylC.sub.1-3 alkyl or aryl wherein aryl is phenyl or naphthyl or phenyl or naphthyl substituted with X; PA0 R.sub.6 is PA0 R.sub.1 is 2-butyl or 2-methyl-2-butyl; PA0 R.sub.4 is CH.sub.3. PA0 (1) 6(R)-[2-[8(R)-(2,2-dimethylbutyryloxy)-2(S)-methyl-6(S)-methyl-7(S)-hydrox y-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrah ydro-2H-pyran-2-one; PA0 (2) 6(R)-[2-[8(R)-(2-methylbutyryloxy)-2(S)-methyl-6(S)-methyl-7(S)-hydroxy-1, 2,6,7,8,8a(R)-hexahydronaphthyl-1-(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydr o-2H-pyran-2-one; PA0 (3) 6(R)-[2-[8(R)-(2,2-dimethylbutyryloxy)-2(S)-methyl-6(S)-methyl-7(S)-hydrox ymethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6- tetrahydro-2H-pyran-2-one; PA0 (4) 6(R)-[2-[8(R)-(2-methylbutyryloxy)-2(S)-methyl-6(S)-methyl-7(S)-hydroxymet hyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetr ahydro-2H-pyran-2-one; PA0 (5) 6(R)-[2-[8(R)-(2,2-dimethylbutyryloxy)-2(S)-methyl-6(S)-methyl-7(R)-methyl -1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahy dro-2H-pyran-2-one; PA0 (6) 6(R)-[2-[8(R)-(2-methylbutyryloxy)-2(S)-methyl-6(S)-methyl-7(R)-methyl-1,2 ,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro- 2H-pyran-2-one; PA0 (7) 6(R)-[2-[8(R)-(2,2-dimethylbutyryloxy)-2(S)-methyl-6(S)-methyl-7(S)-(1(S)- hydroxyethyl)-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3, 4,5,6-tetrahydro-2H-pyran-2-one; PA0 (8) 6(R)-[2-[8(R)-(2-methylbutyryloxy)-2(S)-methyl-6(S)-methyl-7(S)-(1(S)-hydr oxyethyl)-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5, 6-tetrahydro-2H-pyran-2-one; PA0 (9) 6(R)-[2-[8(R)-(2,2-dimethylbutyryloxy)-2(S)-methyl-6(S)-methyl-7(S)-(1(R)- hydroxyethyl)-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3, 4,5,6-tetrahydro-2H-pyran-2-one; PA0 (10) 6(R)-[2-[8(R)-(2-methylbutyryloxy)-2(S)-methyl-6(S)-methyl-7(S)-(1(R)-hydr oxyethyl)-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5, 6-tetrahydro-2H-pyran-2-one; PA0 (11) 6(R)-[2-[8(R)-(2,2-dimethylbutylryloxy)-2(S)-methyl-6(S)-methyl-7(S)-(1(S) -hydroxybenzyl)-1,2,6,7,8,8a,(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy -3,4,5,6-tetrahydro-2H-pyran-2-one; PA0 (12) 6(R)-[2-[8(R)-(2-methylbutyryloxy)-2(S)-methyl-6(S)-methyl-7(S)-(1(S)-hydr oxybenzyl)-1,2,6,7,8,8a,(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4, 5,6-tetrahydro-2H-pyran-2-one; and the corresponding opened dihydroxy acids and esters. PA0 R.sub.5 is ##STR24## C.sub.1-5 alkyl or phenylC.sub.1-3 alkyl; R.sub.7 and R.sub.8 are H, C.sub.1-3 alkyl, phenylC.sub.1-3 alkyl or aryl wherein aryl is phenyl or naphthyl or phenyl or naphthyl substituted with X; PA0 R.sub.6 is PA0 R.sub.1 is 2-butyl or 2-methyl-2-butyl; PA0 R.sub.4 is CH.sub.3.
R.sup.2 is hydrogen or methyl; and a, b, c, and d represent single bonds, one of a, b, c or d represents a double bond, or both a and c or both b and d represent double bonds provided that when a is a double bond, Q is ##STR6## and when d is a double bond, M is ##STR7## and provided that when R.sup.5 or R.sup.6 is OH or OR.sup.7 or X is O, S, or NH, a, b, and c are single bonds. PA2 (a) halogen, PA2 (b) hydroxy, PA2 (c) C.sub.1-10 alkoxy, PA2 (d) C.sub.1-5 alkoxycarbonyl, PA2 (e) C.sub.1-5 acyloxy, PA2 (f) C.sub.3-8 cycloalkyl, PA2 (g) phenyl, PA2 (h) substituted phenyl in which the substituents are X and Y, PA2 (i) C.sub.1-10 alkylS(O).sub.n, PA2 (j) C.sub.3-8 cycloalkylS(O).sub.n, PA2 (k) phenylS(O).sub.n, PA2 (l) substituted phenylS(O).sub.n in which the substituents are X and Y, and PA2 (m) oxo; PA2 (a) C.sub.1-10 alkyl PA2 (b) substituted C.sub.1-10 alkyl in which the substituent is PA2 (c) C.sub.1-10 alkylS(O).sub.n, PA2 (d) C.sub.3-8 cycloalkylS(O).sub.n, PA2 (e) phenylS(O).sub.n, PA2 (f) substituted phenylS(O).sub.n in which the substituents are X and Y, PA2 (g) halogen, PA2 (h) hydroxy, PA2 (i) C.sub.1-10 alkoxy, PA2 (j) C.sub.1-5 alkoxycarbonyl, PA2 (k) C.sub.1-5 acyloxy, PA2 (l) phenyl, and PA2 (m) substituted phenyl in which the substituents are X and Y; PA2 (a) piperidinyl, PA2 (b) pyrrolidinyl, PA2 (c) piperazinyl, PA2 (d) morpholinyl, and PA2 (e) thiomorpholinyl; and PA2 (a) C.sub.1-10 alkyl, PA2 (b) phenyl, and PA2 (c) substituted phenyl in which the substituents are X and Y; PA2 R.sub.5 is ##STR17## phenylC.sub.1-3 alkyl, or C.sub.1-5 alkyl; R.sub.7 and R.sub.8 independently are H, C.sub.1-3 alkyl, phenylC.sub.1-3 alkyl wherein aryl is phenyl, naphthyl, pyridyl, furanyl, thienyl; or phenyl, naphthyl, pyridyl, furanyl or thienyl substituted with groups X and Y; provided that when R.sub.5 is ##STR18## R.sub.7 is not H and when R.sub.5 is ##STR19## neither R.sub.7 nor R.sub.8 is H; (4) R.sub.6 ; PA2 (a) halogen, PA2 (b) hydroxy, PA2 (c) amino; PA2 (d) C.sub.1-5 alkoxy, PA2 (e) C.sub.1-5 alkoxycarbonyl, PA2 (f) C.sub.1-5 alkylacyloxy, PA2 (g) phenylacyloxy, PA2 (h) phenoxycarbonyl, PA2 (i) phenylC.sub.1-5 alkylacyloxy, PA2 (j) phenylC.sub.1-5 alkoxy, PA2 (k) C.sub.1-5 alkylamino, PA2 (l) di(C.sub.1-5 alkyl)amino, PA2 (m) phenylamino, PA2 (n) substituted phenylamino n which the substituents are X and Y, PA2 (o) phenyl C.sub.1-5 alkylamino, PA2 (p) substituted phenyl C.sub.1-5 alkylamino in which the substituents are X and Y, PA2 (q) C.sub.3-8 cycloalkyl, PA2 (r) phenyl, PA2 (s) substituted phenyl in which the substituents are X and Y, PA2 (t) phenylS(O).sub.n, PA2 (u) substituted phenylS(O).sub.n in which the substituents are X and Y, PA2 (v) phenyl-C.sub.1-5 alkyl-S(O).sub.n, PA2 (w) C.sub.1-5 alkylS(O).sub.n, PA2 (x) phenylaminoacyloxy, PA2 (y) C.sub.1-5 alkylaminoacyloxy, PA2 (z) C.sub.1-5 alkylacylamino, PA2 (aa) di(phenylC.sub.1-5 alkyl)phosphonyl, PA2 (bb) di(C.sub.1-5 alkyl)phosphinyl, PA2 (cc) C.sub.1-5 alkyl-carbonyl-, PA2 (dd) carboxy; or PA2 (a) halogen, PA2 (b) hydroxy, PA2 (c) C.sub.1-10 alkoxy, PA2 (d) C.sub.1-5 alkoxycarbonyl, PA2 (e) C.sub.1-5 alkylacyloxy, PA2 (f) phenylacyloxy, PA2 (g) phenoxycarbonyl, PA2 (h) phenyl C.sub.1-5 alkylacyloxy, PA2 (i) phenyl C.sub.1-5 alkoxy, PA2 (j) amino, PA2 (k) C.sub.1-5 alkylamino, PA2 (l) di(C.sub.1-5 alkyl)amino, PA2 (m) phenylamino, PA2 (n) substituted phenylamino in which the substituents are X and Y, PA2 (o) phenyl C.sub.1-5 alkylamino PA2 (p) substituted phenyl C.sub.1-5 alkylamino in which the substituents are X and Y, PA2 (q) C.sub.3-8 cycloalkyl, PA2 (r) phenyl, PA2 (s) substituted phenyl in which the substituents are X and Y, PA2 (t) phenylS(O).sub.n, PA2 (u) substituted phenylS(O).sub.n in which the substituents are X and Y, PA2 (v) phenyl C.sub.1-5 alkyl S(O).sub.n, PA2 (w) C.sub.1-5 alkylS(O).sub.n, PA2 (x) phenylaminoacyloxy, PA2 (y) C.sub.1-5 alkylaminoacyloxy, PA2 (z) C.sub.1-5 alkylacylamino, PA2 (aa) di(phenylC.sub.1-5 alkyl)phosphonyl, PA2 (bb) di(C.sub.1-5 alkyl)phosphinyl, PA2 (a) phenyl, PA2 (b) dimethylamino, and PA2 (c) acetylamino, and PA2 (a) halogen, PA2 (b) hydroxy, PA2 (c) C.sub.1-10 alkoxy, PA2 (d) C.sub.1-5 alkoxycarbonyl, PA2 (e) C.sub.1-5 acyloxy, PA2 (f) C.sub.3-8 cycloalkyl, PA2 (g) phenyl, PA2 (h) substituted phenyl in which the substituents are X and Y, and PA2 (i) oxo; PA2 (a) C.sub.1-10 alkyl, PA2 (b) substituted C.sub.1-10 alkyl in which the substituent is selected from PA2 (c) halogen, PA2 (d) hydroxy, PA2 (e) C.sub.1-10 alkoxy, PA2 (f) C.sub.1-5 alkoxycarbonyl, PA2 (g) C.sub.1-5 acyloxy, PA2 (h) phenyl, PA2 (i) substituted phenyl in which the substituents are X and Y; PA2 R.sub.5 is ##STR20## phenylC.sub.1-3 alkyl, or C.sub.1-5 alkyl; R.sub.7 and R.sub.8 independently are H, C.sub.1-3 alkyl, phenylC.sub.1-3 alkyl or aryl wherein aryl is phenyl, naphthyl, pyridyl, furanyl, thienyl; or phenyl, naphthyl, pyridyl, furanyl or thienyl substituted with groups X and Y; provided that when R.sub.5 is ##STR21## R.sub.7 is not H and when R.sub.5 is ##STR22## neither R.sub.7 nor R.sub.8 is H; or (4) R.sub.6 ; PA2 (a) halogen, PA2 (b) hydroxy, PA2 (c) amino; PA2 (d) C.sub.1-5 alkoxy, PA2 (e) C.sub.1-5 alkoxycarbonyl, PA2 (f) C.sub.1-5 alkylacyloxy, PA2 (g) phenylacyloxy, PA2 (h) phenoxycarbonyl, PA2 (i) phenylC.sub.1-5 alkylacyloxy, PA2 (j) phenylC.sub.1-5 alkoxy, PA2 (k) C.sub.1-5 alkylamino, PA2 (l) di(C.sub.1-5 alkyl)amino, PA2 (m) phenylamino, PA2 (n) substituted phenylamino in which the substituents are X and Y, PA2 (o) phenyl C.sub.1-5 alkylamino, PA2 (p) substituted phenyl C.sub.1-5 alkylamino in which the substituents are X and Y, PA2 (q) C.sub.3-8 cycloalkyl, PA2 (r) phenyl, PA2 (s) substituted phenyl in which the substituents are X and Y, PA2 (t) phenylS(O).sub.n, PA2 (u) substituted phenylS(O).sub.n in which the substituents are X and Y, PA2 (v) phenyl C.sub.1-5 alkyl S(O).sub.n, PA2 (w) C.sub.1-5 alkylS(O).sub.n, PA2 (x) phenylaminoacyloxy, PA2 (y) C.sub.1-5 alkylaminoacyloxy, PA2 (z) C.sub.1-5 alkylacylamino, PA2 (aa) di(phenylC.sub.1-5 alkyl)phosphonyl, PA2 (bb) di(C.sub.1-5 alkyl)phosphinyl, PA2 (cc) C.sub.1-5 alkyl-carbonyl-, PA2 (dd) carboxy-; or PA2 (a) halogen, PA2 (b) hydroxy, PA2 (c) amino; PA2 (a) C.sub.1-5 alkoxy, PA2 (b) C.sub.1-5 alkoxy carbonyl, PA2 (c) C.sub.1-5 alkylacyloxy, PA2 (d) phenylacyloxy, PA2 (e) phenoxycarbonyl, PA2 (f) phenylC.sub.1-5 alkyl, PA2 (g) phenylC.sub.1-5 alkoxy PA2 (h) C.sub.1-5 alkylamino, PA2 (i) di(C.sub.1-5 alkyl)amino, PA2 (j) phenylamino, PA2 (k) substituted phenylamino in which the substituents are X and Y, PA2 (l) phenyl C.sub.1-5 alkylamino, PA2 (m) substituted phenyl C.sub.1-5 alkyl amino in which the substituents are X and Y, PA2 (n) C.sub.3-8 cycloalkyl, PA2 (o) phenyl, PA2 (p) substituted phenyl in which the substituents are X and Y, PA2 (q) phenylS(O).sub.n PA2 (r) substituted phenylS(O).sub.n in which the substituents are X and Y, PA2 (s) phenyl C.sub.1-5 alkylS(O).sub.n, PA2 (t) C.sub.1-5 alkylS(O).sub.n, PA2 (u) phenylaminoacyloxy, PA2 (v) C.sub.1-5 alkylaminoacyloxy, PA2 (w) C.sub.1-5 alkylacylamino, PA2 (x) di(phenylC.sub.1-5 alkyl)phosphonyl, PA2 (y) di(C.sub.1-5 alkyl)phosphinyl; PA2 (1) hydroxy, PA2 (2) amino, PA2 (3) phenyl, PA2 (4) C.sub.1-5 alkyl-carbonyl-, PA2 (5) C.sub.1-5 alkyl-acyloxy, PA2 (6) C.sub.1-5 alkoxycarbonyl-, PA2 (7) carboxy. PA2 (1) hydroxy, PA2 (2) amino, PA2 (3) phenyl, PA2 (4) C.sub.1-5 alkylcarbonyl-, PA2 (5) C.sub.1-5 alkylacyloxy-, PA2 (6) C.sub.1-5 alkoxycarbonyl-, PA2 (7) carboxy.
U.S. Pat. No. 4,517,373 discloses semi-synthetic hydroxy containing compounds represented by the above general formula wherein R* is ##STR8##
U.S. Pat. No. 4,537,859 and U.S. Pat. No. 4,448,979 also disclose semi-synthetic hydroxy-containing compounds represented by the above general formula wherein R* is ##STR9##
These compounds are prepared by the action of certain microorganisms on the corresponding non-hydroxylated substrates. One such organism described in U.S. Pat. No. 4,537,859 is of the genus Nocardia.
U.K. Patent 2,075,013 discloses semi-synthetic hydroxy containing compounds represented by the above general formula wherein R* is: ##STR10## wherein R.sup.1 is H or Me, and R.sup.2 is H or acyl.
U.S. patent application Ser. No. 254,525 filed Oct. 6, 1988 discloses 6-substituted compounds of the above general formula wherein R* is: ##STR11## wherein R is CH.sub.2 OH, ##STR12## and R.sup.1, R.sup.4, R.sup.7, R.sup.8 and R.sup.9 are broadly defined organic moieties.
U.S. Pat. Nos. 4,604,472 and 4,733,003 disclose compounds of the above formula wherein R* is: ##STR13## wherein X represents a hydrogen atom or a 2-methylbutyryl group, Y represents a hydrogen atom or a methyl group and R.sup.1 and R.sup.2 are the same or different and each represents an oxygen atom or a group of formula .dbd.N--OR.sup.3 where R.sup.3 is a hydrogen or alkyl moiety.
Copending U.S. patent application Ser. No. 213,010 filed June 29, 1988 discloses 5-oxygenated compounds of the above general formula wherein R* is ##STR14## R.sup.4 is H, alkyl or substituted alkyl and R.sup.5 and R.sup.6 are H, OH or OR.sup.7 where R.sup.7 represents a phosphoryl or acyl moiety.
Copending U.S. patent application Ser. No. 212,767 filed June 29, 1988 discloses 5-Oxa, Thia and Aza compounds of the above general formula where R* is: ##STR15## R.sup.1 is an alkyl or substituted alkyl group, R.sup.2 and R.sup.3 are H, alkyl or substituted alkyl and X is O, S(O).sub.n or NR.sup.4 where R.sup.4 is H, alkyl or substituted alkyl.